DESCRIPTION: Transforming Growth Factor beta (TGFbeta) induces extra cellular matrix (ECM) remodeling, inhibits cellular proliferation and suppresses malignant behavior. TGFbeta, however, has also been reported to stimulate malignant behavior. It is not clear how ECM remodeling is integrated into the TGFbeta function. The Principal Investigator has unified several hypotheses to integrate ECM remodeling, through intergin activation at focal adhesion contacts, with the tumor-suppression pathway of E-cadherin activation or the tumor-promoting pathway of beta- catenin activation. The long term objective of this application is to determine how ECM remodeling is integrated into the function of TGFbeta. The proposed hypotheses and specific aims are: Hypothesis I: TGFbeta-induced ECM remodeling activates integrin-dependent signaling at focal adhesion contacts and links with the antiproliferative and tumor-suppressive pathways of E-cadherin activation. Specific Aim 1: Determine how ECM remodeling and integrin signaling leads to the induction of E-Cadherin by TGFbeta; investigate the functional significance of E-cadherin in the antiproliferative and tumor-suppressive action of TGFbeta. Hypothesis II: TGFbeta-induced beta-catenin, if undegradated, is an underlying mechanism by which TGFbeta stimulates malignant cell behavior. Specific Aim 2: Determine how beta-catenin is activated and the functional significance of beta-catenin induction and its complex formation with adenomatous polyposis coli (APC) to bring about tumor-suppressive behavior.